The field of the invention relates to methods for treating cancers. In particular, the field of the invention relates to methods, compounds, and compositions for treating cancers characterized by rearrangements in the mixed lineage leukemia gene, otherwise referred to as “MLL-r cancers,” including MLL-r leukemias. The methods, compounds, and compositions disclosed herein relate to the use of therapeutic agents that inhibit the biological activity of one or more members of the interleukin-1 signaling pathway, such as inhibitors of interleukin-1 receptor kinase 4 (IRAK4).
Rearrangements or translocations of the mixed lineage leukemia gene (MLL-r) have been shown to be associated with aggressive forms of leukemia. Cases of acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) that are characterized by MLL-r are extremely aggressive and are predominantly seen in infants and in therapy-related leukemias. In contrast to other types of leukemias, the prognosis for MLL-r is dismal and despite advances in new therapies, cure rates have plateaued over the last several years. Therefore, new therapies are needed.
Chromosomal rearrangements involving translocations between one copy of 11q23 and another chromosome can generate oncogenic fusion proteins consisting of an n-terminal portion of MLL and c-terminal portion of the fusion partner. The normal in vivo function of MLL is as the enzymatic subunit of a COMPASS-like complex that methylates histone H3 on its fourth lysine. The chimeric protein lacks the c-terminal methyltransferase, but gains properties of the c-terminal fusion partner. Since many of the translocation partners are transcriptional activators, the aberrant recruitment of the translocation partner to normal MLL targets, which include oncogenes, drives leukemogenesis. Despite the chromosomal translocation, one wild-type copy of the MLL gene exists but the protein levels expressed from this allele are much lower than the MLL chimeric protein. Therefore, the present inventors hypothesized that a decrease in wild-type MLL protein observed in MLL-r may contribute to the development of leukemia.
Here, the inventors have shown that the wild-type MLL protein is decreased in MLL-r leukemia cells. Further, the inventors have shown that the interleukin-1 signaling pathway regulates the turnover of MLL protein. By administering inhibitors of the interleukin-1 signaling pathway to leukemia cells lines, including inhibitors of IRAK4, the inventors have determined that levels of wild-type MLL protein can be increased and growth of MLL-r leukemia cells can be inhibited. Furthermore, inhibitors of inhibitors of the interleukin-1 signaling pathway, including inhibitors of IRAK4, increased survival in a murine leukemia model. In addition to studying inhibitors of the interleukin-1 signaling pathway known in the art, the inventors also synthesized new inhibitors of IRAK4. By administering the new inhibitors of IRAK4 leukemia cells, the inventors have determined that levels of wild-type MLL protein can be increased and growth of MLL-r leukemia cells can be inhibited The inventors' results have implications for MLL-r leukemias as well as other types of cancers which are shown to be characterized by MLL-r.